The antidepressant-like effect of guanosine involves the modulation of adenosine A1 and A2A receptors.

Guanosine has been considered a promising candidate for antidepressant responses, but if this nucleoside could modulate adenosine A1 (A1R) and A2A (A2AR) receptors to exert antidepressant-like actions remains to be elucidated. This study investigated the role of A1R and A2AR in the antidepressant-like response of guanosine in the mouse tail suspension test and molecular interactions between guanosine and A1R and A2AR by docking analysis. The acute (60 min) administration of guanosine (0.05 mg/kg, p.o.) significantly decreased the immobility time in the tail suspension test, without affecting the locomotor performance in the open-field test, suggesting an antidepressant-like effect. This behavioral response was paralleled with increased A1R and reduced A2AR immunocontent in the hippocampus, but not in the prefrontal cortex, of mice. Guanosine-mediated antidepressant-like effect was not altered by the pretreatment with caffeine (3 mg/kg, i.p., a non-selective adenosine A1R/A2AR antagonist), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX - 2 mg/kg, i.p., a selective adenosine A1R antagonist), or 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)-phenol (ZM241385 - 1 mg/kg, i.p., a selective adenosine A2AR antagonist). However, the antidepressant-like response of guanosine was completely abolished by adenosine (0.5 mg/kg, i.p., a non-selective adenosine A1R/A2AR agonist), N-6-cyclohexyladenosine (CHA - 0.05 mg/kg, i.p., a selective adenosine A1 receptor agonist), and N-6-[2-(3,5-dimethoxyphenyl)-2-(methylphenyl)ethyl]adenosine (DPMA - 0.1 mg/kg, i.p., a selective adenosine A2A receptor agonist). Finally, docking analysis also indicated that guanosine might interact with A1R and A2AR at the adenosine binding site. Overall, this study reinforces the antidepressant-like of guanosine and unveils a previously unexplored modulation of the modulation of A1R and A2AR in its antidepressant-like effect.

Neuroinflammation in Alzheimer's disease: potential beneficial effects of vitamin D.

Alzheimer's disease (AD) is the most common cause of dementia. In recent years, several studies have robustly shown that neuroinflammation plays a crucial role in the pathophysiology of this disease. The co-localization of amyloid-ß plaques near activated glial cells and the increased levels of inflammatory cytokines in AD patients indicate the involvement of the neuroinflammatory process in AD progression. Considering that pharmacological treatment remains a challenge for the management of this disease, compounds with anti-inflammatory and antioxidant properties are promising therapeutic strategies. In this context, vitamin D has gained attention in the last few years due to its neuroprotective property and the high prevalence of vitamin D deficiency in the population. Herein, in this narrative review we present the possible contribution of the antioxidant and anti-inflammatory properties of vitamin D for its neuroprotective effects, and the clinical and preclinical data dealing with the effects of vitamin D in AD, focusing mainly on the neuroinflammatory process.

The antidepressant-like effect elicited by vitamin D3 is associated with BDNF/TrkB-related synaptic protein synthesis.

Vitamin D3 (cholecalciferol) has been shown to exert antidepressant-like responses, but the role BDNF/TrkB-related synaptic plasticity in this effect remains to be established. Thus, this study investigated the time-course antidepressant-like response of vitamin D3 in female and male mice and the possible role of BDNF/TrkB signaling in this response. The repeated (7 and 21 days), but not acute (60 min), administration of vitamin D3 (2.5 µg/kg, p.o.) exerted an antidepressant-like effect in female and male mice subjected to the tail suspension test, without altering the basal locomotor activity in the open-field test. Notably, vitamin D3 caused a similar time-dependent antidepressant-like effect in male and female mice, suggesting that this behavioral response in the tail suspension test might not be affected by sex differences. Vitamin D3 administration for 21 days, but not for 7 days or 1 h, augmented BDNF levels in the hippocampus and prefrontal cortex of mice. No effects on phospho-CREB/CREB levels were detected in the hippocampus and prefrontal cortex after chronic vitamin D3 administration. Additionally, vitamin D3 increased TrkB, GluA1, and PSD-95 levels in the prefrontal cortex, but not in the hippocampus. Furthermore, an upregulation of synapsin level was observed in both brain regions after vitamin D3 administration. These findings reinforce and extend the notion that vitamin D3 is effective to produce antidepressant-like responses in male and female mice and provide novel evidence that this effect could be associated with BDNF/TrkB-related synaptic protein synthesis. Finally, vitamin D3 could be a feasible nutritional strategy for the management of depression.

Major Depressive Disorder and Gut Microbiota: Role of Physical Exercise.

Major depressive disorder (MDD) has a high prevalence and is a major contributor to the global burden of disease. This psychiatric disorder results from a complex interaction between environmental and genetic factors. In recent years, the role of the gut microbiota in brain health has received particular attention, and compelling evidence has shown that patients suffering from depression have gut dysbiosis. Several studies have reported that gut dysbiosis-induced inflammation may cause and/or contribute to the development of depression through dysregulation of the gut-brain axis. Indeed, as a consequence of gut dysbiosis, neuroinflammatory alterations caused by microglial activation together with impairments in neuroplasticity may contribute to the development of depressive symptoms. The modulation of the gut microbiota has been recognized as a potential therapeutic strategy for the management of MMD. In this regard, physical exercise has been shown to positively change microbiota composition and diversity, and this can underlie, at least in part, its antidepressant effects. Given this, the present review will explore the relationship between physical exercise, gut microbiota and depression, with an emphasis on the potential of physical exercise as a non-invasive strategy for modulating the gut microbiota and, through this, regulating the gut-brain axis and alleviating MDD-related symptoms.

Functional role of ascorbic acid in the central nervous system: a focus on neurogenic and synaptogenic processes.

Ascorbic acid, a water-soluble vitamin, is highly concentrated in the brain and participates in neuronal modulation and regulation of central nervous system (CNS) homeostasis. Ascorbic acid has emerged as a neuroprotective compound against neurotoxicants and neurodegenerative diseases, including Alzheimer's disease, multiple sclerosis and amyotrophic lateral sclerosis. Moreover, it improves behavioral and biochemical alterations in psychiatric disorders, including schizophrenia, anxiety, major depressive disorder, and bipolar disorder. Some recent studies have advanced the knowledge on the mechanisms associated with the preventive and therapeutic effects of ascorbic acid by showing that they are linked to improved neurogenesis and synaptic plasticity. This review shows that ascorbic acid has the potential to regulate positively stem cell generation and proliferation. Moreover, it improves neuronal differentiation of precursors cells, promotes adult hippocampal neurogenesis, and has synaptogenic effects that are possibly linked to its protective or therapeutic effects in the brain.

Vitamin E for the management of major depressive disorder: possible role of the anti-inflammatory and antioxidant systems.

OBJECTIVES: Vitamin E has various functions in humans, including antioxidant, anti-inflammatory, anti-cancer, and anti-atherogenic actions, as well as direct effects on enzymatic activities and modulation of gene transcription. In addition to these functions, vitamin E is also important for the central nervous system, and its role in the prevention and/or treatment of some neurological diseases has been suggested. In particular, the role of vitamin E in the modulation of major depressive disorder (MDD) is an issue that has emerged in recent studies. Many factors have been implicated in the pathophysiology of this disorder, including inflammation, oxidative, and nitrosative stress. METHODS: This narrative review discusses the involvement of inflammation, oxidative, and nitrosative stress in the pathophysiology of MDD and presents clinical and preclinical studies that correlate vitamin E with this psychiatric disorder. RESULTS: We gathered evidence from clinical studies that demonstrated the relationship between low vitamin E status and MDD symptoms. Vitamin E has been reported to exert a beneficial influence on the oxidative and inflammatory status of individuals, factors that may account for the attenuation of depressive symptoms. Preclinical studies have reinforced the antidepressant-like response of vitamin E, and the mechanisms underlying its effect seem to be related to the modulation of oxidative stress and neuroinflammation. CONCLUSION: We suggest that vitamin E has potential to be used as an adjuvant for the management of MDD, but more studies are clearly needed to ascertain the efficacy of vitamin E for alleviating depressive symptoms.

Involvement of serotonergic neurotransmission in the antidepressant-like effect elicited by cholecalciferol in the chronic unpredictable stress model in mice.

Cholecalciferol deficiency has been associated with stress-related psychiatric disorders, particularly depression. Therefore, the present study investigated the antidepressant-like effect of cholecalciferol in female mice and the possible role of the serotonergic system in this response. The ability of cholecalciferol to elicit an antidepressant-like effect and to modulate serotonin levels in the hippocampus and prefrontal cortex of mice subjected to chronic unpredictable stress (CUS) was also investigated. The administration of cholecalciferol (2.5, 7.5, and 25 µg/kg, p.o.) for 7 days, similar to fluoxetine (10 mg/kg, p.o., serotonin reuptake inhibitor), reduced the immobility time in the tail suspension test, without altering the locomotor performance in the open-field test. Moreover, the administration of p-chlorophenylalanine methyl ester (PCPA - 100 mg/kg, i.p., for 4 days, a selective inhibitor of tryptophan hydroxylase, involved in the serotonin synthesis) abolished the antidepressant-like effect of cholecalciferol and fluoxetine in the tail suspension test, demonstrating the involvement of serotonergic system. Additionally, CUS protocol (21 days) induced depressive-like behavior in the tail suspension test and decreased serotonin levels in the prefrontal cortex and hippocampus of mice. Conversely, the administration of cholecalciferol and fluoxetine in the last 7 days of CUS protocol completely abolished the stress-induced depressive-like phenotype. Cholecalciferol was also effective to abrogate CUS-induced reduction on serotonin levels in the prefrontal cortex, but not in the hippocampus. Our results indicate that cholecalciferol has an antidepressant-like effect in mice by modulating the serotonergic system and support the assumption that cholecalciferol may have beneficial effects for the management of depression.

Molecular Basis Underlying the Therapeutic Potential of Vitamin D for the Treatment of Depression and Anxiety.

Major depressive disorder and anxiety disorders are common and disabling conditions that affect millions of people worldwide. Despite being different disorders, symptoms of depression and anxiety frequently overlap in individuals, making them difficult to diagnose and treat adequately. Therefore, compounds capable of exerting beneficial effects against both disorders are of special interest. Noteworthily, vitamin D deficiency has been associated with an increased risk of developing depression and anxiety, and individuals with these psychiatric conditions have low serum levels of this vitamin. Indeed, in the last few years, vitamin D has gained attention for its many functions that go beyond its effects on calcium-phosphorus metabolism. Particularly, antioxidant, anti-inflammatory, pro-neurogenic, and neuromodulatory properties seem to contribute to its antidepressant and anxiolytic effects. Therefore, in this review, we highlight the main mechanisms that may underlie the potential antidepressant and anxiolytic effects of vitamin D. In addition, we discuss preclinical and clinical studies that support the therapeutic potential of this vitamin for the management of these disorders.

Antidepressant-like effect of guanosine involves activation of AMPA receptor and BDNF/TrkB signaling.

Guanosine is a purine nucleoside that has been shown to exhibit antidepressant effects, but the mechanisms underlying its effect are not well established. We investigated if the antidepressant-like effect induced by guanosine in the tail suspension test (TST) in mice involves the modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, voltage-dependent calcium channel (VDCC), and brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) pathway. We also evaluated if the antidepressant-like effect of guanosine is accompanied by an acute increase in hippocampal and prefrontocortical BDNF levels. Additionally, we investigated if the ability of guanosine to elicit a fast behavioral response in the novelty suppressed feeding (NSF) test is associated with morphological changes related to hippocampal synaptogenesis. The antidepressant-like effect of guanosine (0.05 mg/kg, p.o.) in the TST was prevented by DNQX (AMPA receptor antagonist), verapamil (VDCC blocker), K-252a (TrkBantagonist), or BDNF antibody. Increased P70S6K phosphorylation and higher synapsin I immunocontent in the hippocampus, but not in the prefrontal cortex, were observed 1 h after guanosine administration. Guanosine exerted an antidepressant-like effect 1, 6, and 24 h after its administration, an effect accompanied by increased hippocampal BDNF level. In the prefrontal cortex, BDNF level was increased only 1 h after guanosine treatment. Finally, guanosine was effective in the NSF test (after 1 h) but caused no alterations in dendritic spine density and remodeling in the ventral dentate gyrus (DG). Altogether, the results indicate that guanosine modulates targets known to be implicated in fast antidepressant behavioral responses (AMPA receptor, VDCC, and TrkB/BDNF pathway).

Ursolic acid abrogates depressive-like behavior and hippocampal pro-apoptotic imbalance induced by chronic unpredictable stress.

Emerging evidence has shown that ursolic acid exerts antidepressant-like effects, however, its ability to elicit an antidepressant-like response in rodents subjected to stress model that mimics behavioral and neurochemical alterations found in depression remains to be determined. Thus, this study investigated the possible antidepressant-like effect of ursolic acid in mice subjected to chronic unpredictable stress (CUS) for 14 days, and whether this effect could be associated with the modulation of serum corticosterone levels and hippocampal Bcl-2/Bax mRNA expression. Our results indicated that CUS induced a depressive-like behavior, as demonstrated by an increase in the immobility time and latency to first grooming in the tail suspension test and splash test, respectively. Conversely, the repeated administration of ursolic acid (0.1 mg/kg, p.o.) or fluoxetine (10 mg/kg, p.o.) in the last 7 days of CUS completely prevented CUS-induced behavioral alterations, suggesting an antidepressant-like effect. Additionally, CUS significantly increased the mRNA expression of Bax (pro-apoptosis marker), but not Bcl-2 (anti-apoptosis marker) in the hippocampus. Moreover, reduced hippocampal mRNA expression of Bcl-2/Bax ratio was detected in CUS-exposed mice. Ursolic acid, but not fluoxetine, prevented CUS-induced increase in the expression of Bax, but both ursolic acid and fluoxetine prevented CUS-induced reduction on Bcl-2/Bax ratio. Furthermore, neither CUS nor treatments with ursolic acid or fluoxetine altered serum corticosterone levels. Our study unveils the ability of ursolic acid to prevent the depressive-like behavior induced by stress and the modulation of Bcl-2/Bax expression could be associated with this response.

Physical exercise prevents amyloid ß1-40-induced disturbances in NLRP3 inflammasome pathway in the hippocampus of mice.

Amyloid beta (Aß), one of the main hallmarks of Alzheimer's Disease (AD), may stimulate pattern recognition receptors (PRR) such as the NLRP3 inflammasome, inducing a pro-inflammatory state in the brain that contributes to disease development. Physical exercise can have multiple beneficial effects on brain function, including anti-inflammatory and neuroprotective roles. The objective of this study was to investigate the prophylactic effect of moderate treadmill exercise for 4 weeks on inflammatory events related to NLRP3 signaling in the hippocampus of mice after intracerebroventricular Aß1-40 administration. Our results show that Aß1-40 administration (400 pmol/mouse, i.c.v.) significantly increased the immunocontent Iba-1 (a microglial reactivity marker), NLRP3, TXNIP, and caspase-1 in the hippocampus of mice. However, physical exercise prevented the hippocampal increase in Iba-1, TXNIP, and activation of the NLRP3 inflammasome pathway caused by Aß1-40. Moreover, physical exercise per se reduced the TXNIP and caspase-1 immunocontent in the hippocampus. No alterations were observed on the immunocontent of GFAP, ASC, and IL-1ß in the hippocampus after Aß1-40 and/or physical exercise. These results reinforce the role of NLRP3 inflammasome pathway in AD and point to physical exercise as a possible non-pharmacological strategy to prevent inflammatory events triggered by Aß1-40 in mice.

Ketamine, but not fluoxetine, rapidly rescues corticosterone-induced impairments on glucocorticoid receptor and dendritic branching in the hippocampus of mice.

Although numerous studies have investigated the mechanisms underlying the fast and sustained antidepressant-like effects of ketamine, the contribution of the glucocorticoid receptor (GR) and dendritic branching remodeling to its responses remain to be fully established. This study investigated the ability of a single administration of ketamine to modulate the GR and dendritic branching remodeling and complexity in the hippocampus of mice subjected to chronic corticosterone (CORT) administration. CORT was administered for 21 days, followed by a single administration of ketamine (1 mg ∕kg, i.p.) or fluoxetine (10 mg ∕kg, p.o., conventional antidepressant) in mice. On 22nd, 24 h after the treatments, GR immunocontent in the hippocampus was analyzed by western blotting, while the dendritic arborization and dendrite length in the ventral and dorsal dentate gyrus (DG) of the hippocampus was analyzed by Sholl analysis. Chronic CORT administration downregulated hippocampal GR immunocontent, but this alteration was completely reversed by a single administration of ketamine, but not fluoxetine. Moreover, CORT administration significantly decreased dendritic branching in the dorsal and ventral DG areas and caused a mild decrease in dendrite length in both regions. Ketamine, but not fluoxetine, reversed CORT-induced dendritic branching loss in the ventral and dorsal DG areas, regions associated with mood regulation and cognitive functions, respectively. This study provides novel evidence that a single administration of ketamine, but not fluoxetine, rescued the impairments on GR and dendritic branching in the hippocampus of mice subjected to chronic CORT administration, effects that may be associated with its rapid antidepressant response.

Neuronal activity regulated pentraxin (narp) and GluA4 subunit of AMPA receptor may be targets for fluoxetine modulation.

Fluoxetine is the foremost prescribed antidepressant. Drugs acting on monoaminergic system may also regulate glutamatergic system. Indeed, the investigation of proteins associated with this system, such as Narp (neuronal activity-dependent pentraxin) and GluA4 subunit of AMPA receptor may reveal poorly explored modulations triggered by conventional antidepressants. This study aimed to uncover neurochemical mechanisms underlying the chronic fluoxetine treatment, mainly by evaluating these protein targets in the prefrontal cortex and in the hippocampus. Mice received a daily administration of fluoxetine (0.1, 1 or 10 mg/kg, p.o.) or potable water (vehicle group) for 21 days. These animals were submitted to the forced swim test (FST) to verify antidepressant-like responses and the open-field test (OFT) to assess locomotor activity. Modulation of signaling proteins was analyzed by western blot. Chronic treatment with fluoxetine (1 and 10 mg/kg) was effective, since it reduced the immobility time in the FST, without altering locomotor activity. Fluoxetine 10 mg/kg increased CREB phosphorylation and BDNF expression in the prefrontal cortex and hippocampus. Noteworthy, in the hippocampus fluoxetine also promoted Akt activation and augmented Narp expression. In the prefrontal cortex, a significant decrease in the expression of the GluA4 subunit and Narp were observed following fluoxetine administration (10 mg/kg). The results provide evidence of novel molecular targets potentially involved in the antidepressant effects of fluoxetine, since in mature rodents Narp and GluA4 are mainly expressed in the GABAergic parvalbumin-positive (PV+) interneurons. This may bring new insights into the molecular elements involved in the mechanisms underlying the antidepressant effects of fluoxetine.

Antidepressant-like and pro-neurogenic effects of physical exercise: the putative role of FNDC5/irisin pathway.

Physical exercise has been shown to exert antidepressant effects, but the mechanisms underlying this effect are not completely elucidated. Therefore, we aimed at investigating the antidepressant, pro-neurogenic, and neuroprotective effects of physical exercise and the possible role of FNDC5/irisin for this effect. Treadmill running was used as a protocol of physical exercise (45 min/day/5 days/week for 4 weeks) in female Swiss mice. Immobility time was registered in the tail suspension test (TST) and forced swim test (FST). Immunohistochemical analyses to evaluate hippocampal cell proliferation, neuronal survival, and neuronal commitment and maturation, as well as expression of FNDC5 C-terminal fragment were performed in the entire, dorsal, and ventral dentate gyrus (DG) of the hippocampus. Fluoro-Jade B staining was performed to evaluate degenerating neurons in DG. FNDC5 C-terminal and FNDC5/irisin immunocontents were analyzed by western blot. Exposure to physical exercise reduced the immobility time both in the TST and the FST. This antidepressant-like effect was accompanied by an increase in hippocampal cell proliferation, hippocampal neuronal differentiation, and neuronal survival in the dorsal and ventral DG. Fluoro-Jade B staining was reduced in entire and dorsal DG in exercised mice. Finally, physical exercise also resulted in increased number of FNDC5-positive cells in the hippocampal DG as well as elevated FNDC5 C-terminal and FNDC5/irisin immunocontent in the entire hippocampus. The results suggest that the FNDC5 C-terminal fragment/irisin pathway may be implicated in the antidepressant-like, pro-neurogenic, and neuroprotective effects of treadmill running.

Protective Effects of Ursolic Acid Against Cytotoxicity Induced by Corticosterone: Role of Protein Kinases.

Neuronal hippocampal death can be induced by exacerbated levels of cortisol, a condition usually observed in patients with Major depressive disorder (MDD). Previous in vitro and in vivo studies showed that ursolic acid (UA) elicits antidepressant and neuroprotective properties. However, the protective effects of UA against glucocorticoid-induced cytotoxicity have never been addressed. Using an in vitro model of hippocampal cellular death induced by elevated levels of corticosterone, we investigated if UA prevents corticosterone-induced cytotoxicity in HT22 mouse hippocampal derived cells. Concentrations lower than 25 µM UA did not alter cell viability. Co-incubation with UA for 48 h was able to protect HT22 cells from the reduction on cell viability and from the increase in apoptotic cells induced by corticosterone. Inhibition of protein kinase A (PKA), protein kinase C (PKC) and, Ca2+/calmodulin-dependent protein kinase II (CaMKII), but not phosphoinositide 3-kinase(PI3K), by using the pharmacological the inhibitors: H-89, chelerythrine, KN-62, and LY294002, respectively totally abolished the cytoprotective effects of UA. Finally, UA abrogated the reduction in phospho-extracellular signal-regulated kinases 1 and 2 (ERK1/2) but not in phospho-c-Jun kinases induced by corticosterone. These results indicate that the protective effect of UA against the cytotoxicity induced by corticosterone in HT22 cells may involve PKA, PKC, CaMKII, and ERK1/2 activation. The cytoprotective potential of UA against corticosterone-induced cytotoxicity and its ability to modulate intracellular signaling pathways involved in cell proliferation and survival suggest that UA may be a relevant strategy to manage stress-related disorders such as MDD.

The antidepressant-like effect of guanosine is dependent on GSK-3ß inhibition and activation of MAPK/ERK and Nrf2/heme oxygenase-1 signaling pathways.

Although guanosine is an endogenous nucleoside that displays antidepressant-like properties in several animal models, the mechanism underlying its antidepressant-like effects is not well characterized. The present study aimed at investigating the involvement of ERK/GSK-3ß and Nrf2/HO-1 signaling pathways in the antidepressant-like effect of guanosine in the mouse tail suspension test (TST). The immobility time in the TST was taken as an indicative of antidepressant-like responses and the locomotor activity was assessed in the open-field test. Biochemical analyses were performed by Western blotting in the hippocampus and prefrontal cortex (PFC). The combined treatment with sub-effective doses of guanosine (0.01 mg/kg, p.o.) and lithium chloride (a non-selective GSK-3ß inhibitor, 10 mg/kg, p.o.) or AR-A014418 (selective GSK-3ß inhibitor, 0.01 µg/site, i.c.v.) produced a synergistic antidepressant-like effect in the TST. The antidepressant-like effect of guanosine (0.05 mg/kg, p.o.) was completely prevented by the treatment with MEK1/2 inhibitors U0126 (5 µg/site, i.c.v.), PD98059 (5 µg/site, i.c.v.), or zinc protoporphyrin IX (ZnPP) (HO-1 inhibitor, 10 µg/site, i.c.v). Guanosine administration (0.05 mg/kg, p.o.) increased the immunocontent of ß-catenin in the nuclear fraction and Nrf2 in the cytosolic fraction in the hippocampus and PFC. The immunocontent of HO-1 was also increased in the hippocampus and PFC. Altogether, the results provide evidence that the antidepressant-like effect of guanosine in the TST involves the inhibition of GSK-3ß, as well as activation of MAPK/ERK and Nrf2/HO-1 signaling pathways, highlighting the relevance of these molecular targets for antidepressant responses.

Levels of 25-hydroxyvitamin D3, biochemical parameters and symptoms of depression and anxiety in healthy individuals.

Growing evidence support the role of vitamin D in brain function and behavior. This study investigated the relationship between 25-hydroxyvitamin D3 [25(OH)D3] levels, biochemical profile and symptoms of depression and anxiety in healthy individuals. Symptoms of depression were assessed by the Beck Depression Inventory (BDI) and anxiety was evaluated with the State-Trait Anxiety Inventory (STAI). Our sample included 36 individuals, mostly women 27(75%), 36.39 ± 9.72 years old, non-smokers 31(86.1%), body mass index of 26.57 ± 3.92 kg/m2, 27.95 ± 7.50% body fat. Participants were divided into those with 25(OH)D3 levels lower than 40 ng/mL (mean 28.16 ± 7.07) and equal or higher than 40 ng/mL (mean 53.19 ± 6.32). Those with lower 25(OH)D3 had higher levels of triacylglycerol, triacylglycerol/high density lipoprotein (HDL) ratio, high glucose and homeostatic model assessment of insulin resistance (HOMA-IR) index. No changes were observed in sociodemographic variables, body composition, inflammatory parameters and cortisol. Additionally, in the groups with low and high 25(OH)D3 levels, STAI state, STAI trait and BDI scores were not statistically different. Levels of 25(OH)D3 were inversely and independently associated with glucose and HOMA-IR, but not associated with triacylglycerol, depression and anxiety scores. Lower levels of 25(OH)D3 were associated with dysfunction in glucose metabolism but not with depression and anxiety in healthy individuals.

Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress.

The consumption of caffeine (an adenosine receptor antagonist) correlates inversely with depression and memory deterioration, and adenosine A2A receptor (A2AR) antagonists emerge as candidate therapeutic targets because they control aberrant synaptic plasticity and afford neuroprotection. Therefore we tested the ability of A2AR to control the behavioral, electrophysiological, and neurochemical modifications caused by chronic unpredictable stress (CUS), which alters hippocampal circuits, dampens mood and memory performance, and enhances susceptibility to depression. CUS for 3 wk in adult mice induced anxiogenic and helpless-like behavior and decreased memory performance. These behavioral changes were accompanied by synaptic alterations, typified by a decrease in synaptic plasticity and a reduced density of synaptic proteins (synaptosomal-associated protein 25, syntaxin, and vesicular glutamate transporter type 1), together with an increased density of A2AR in glutamatergic terminals in the hippocampus. Except for anxiety, for which results were mixed, CUS-induced behavioral and synaptic alterations were prevented by (i) caffeine (1 g/L in the drinking water, starting 3 wk before and continued throughout CUS); (ii) the selective A2AR antagonist KW6002 (3 mg/kg, p.o.); (iii) global A2AR deletion; and (iv) selective A2AR deletion in forebrain neurons. Notably, A2AR blockade was not only prophylactic but also therapeutically efficacious, because a 3-wk treatment with the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) reversed the mood and synaptic dysfunction caused by CUS. These results herald a key role for synaptic A2AR in the control of chronic stress-induced modifications and suggest A2AR as candidate targets to alleviate the consequences of chronic stress on brain function.

Antidepressant Effects of Probucol on Early-Symptomatic YAC128 Transgenic Mice for Huntington's Disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a trinucleotide expansion in the HD gene, resulting in an extended polyglutamine tract in the protein huntingtin. HD is traditionally viewed as a movement disorder, but cognitive and neuropsychiatric symptoms also contribute to the clinical presentation. Depression is one of the most common psychiatric disturbances in HD, present even before manifestation of motor symptoms. Diagnosis and treatment of depression in HD-affected individuals are essential aspects of clinical management in this population, especially owing to the high risk of suicide. This study investigated whether chronic administration of the antioxidant probucol improved motor and affective symptoms as well as hippocampal neurogenic function in the YAC128 transgenic mouse model of HD during the early- to mild-symptomatic stages of disease progression. The motor performance and affective symptoms were monitored using well-validated behavioral tests in YAC128 mice and age-matched wild-type littermates at 2, 4, and 6 months of age, after 1, 3, or 5 months of treatment with probucol (30 mg/kg/day via water supplementation, starting on postnatal day 30). Endogenous markers were used to assess the effect of probucol on cell proliferation (Ki-67 and proliferation cell nuclear antigen (PCNA)) and neuronal differentiation (doublecortin (DCX)) in the hippocampal dentate gyrus (DG). Chronic treatment with probucol reduced the occurrence of depressive-like behaviors in early- and mild-symptomatic YAC128 mice. Functional improvements were not accompanied by increased progenitor cell proliferation and neuronal differentiation. Our findings provide evidence that administration of probucol may be of clinical benefit in the management of early- to mild-symptomatic HD.

NLRP3 inflammasome-driven pathways in depression: Clinical and preclinical findings.

Over the past three decades, an intricate interaction between immune activation, release of pro-inflammatory cytokines and changes in brain circuits related to mood and behavior has been described. Despite extensive efforts, questions regarding when inflammation becomes detrimental or how we can target the immune system to develop new therapeutic strategies for the treatment of psychiatric disorders remain unresolved. In this context, novel aspects of the neuroinflammatory process activated in response to stressful challenges have recently been documented in major depressive disorder (MDD). The Nod-like receptor pyrin containing 3 inflammasome (NLRP3) is an intracellular multiprotein complex responsible for a number of innate immune processes associated with infection, inflammation and autoimmunity. Recent data have demonstrated that NLRP3 activation appears to bridge the gap between immune activation and metabolic danger signals or stress exposure, which are key factors in the pathogenesis of psychiatric disorders. In this review, we discuss both preclinical and clinical evidence that links the assembly of the NLRP3 complex and the subsequent proteolysis and release of the pro-inflammatory cytokines interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) in chronic stress models and patients with MDD. Importantly, we also focus on the therapeutic potential of targeting the NLRP3 inflammasome complex to improve stress resilience and depressive symptoms.